Curr Urol Rep (2015) 16: 84

DOI 10.1007/s11934-015-0553-3

MEN’S HEALTH (R CARRION AND C YANG, SECTION EDITORS)

The Challenge of Erectile Dysfunction Management

in the Young Man
Seth D. Cohen 1

Published online: 13 November 2015

# Springer Science+Business Media New York 2015

Abstract Erectile dysfunction (ED) in a young man is an Keywords Erectile dysfunction . Men’s health . Sexual
important health problem that significantly impacts the pa- medicine
tient’s quality of life and can have a detrimental effect on his
well-being and relationship with his partner. Erectile dysfunc-
tion or impotence is one of the few disorders that will bring a Introduction
young man into the doctor’s office. This review article focuses
on the epidemiology, etiology, presentation, work-up, and Erectile dysfunction (ED) in a young man is an important
treatment of young men (age ~20–40 years old) presenting health problem that significantly impacts the patient’s quality
with complaints of ED. It is important to identify the precise of life and can have a detrimental effect on his well-being and
etiology of the ED before proceeding with further evaluation relationship with his partner. Erectile dysfunction or impo-
and treatment because the work-up can be invasive and costly. tence is one of the few disorders that will bring a young man
ED is estimated to affect 20 % of men above 40 years of age, into the doctor’s office. ED can be a severely debilitating
with the incidence increasing with increasing age. Erectile disease, thus most patients with chronic erectile dysfunction
dysfunction has traditionally been seen as an age-dependent should be screened for other mental health disorders like de-
problem; however, approximately 2 % of men are affected at pression and performance anxiety.
40 years of age but this may be a gross underestimation sec- ED typically presents in the fifth and sixth decade of a man’s
ondary to reporting bias. Because ED is traditionally seen in life; however, sexual health providers are seeing more and more
the aging male population, studies regarding ED tend to be young men, especially those with multiple comorbidities, pre-
more frequently carried out among middle-aged and elderly senting to the office sooner with symptoms of ED. Although
men rather than in young men. These studies underline how the prevalence of organic ED increases with age, a significant
comorbidities such as diabetes mellitus, cardiovascular or cohort of men under the age of 40 also suffers from organic ED
neurological pathologies, and medication use are strongly from various conditions including but not limited to trauma.
linked with ED. In addition, ED has been described to be This review article will focus on the epidemiology, etiolo-
associated with obesity or physical inactivity. This review gy, presentation, work-up, and treatment of young men (age
article summarizes the important information that all sexual ~20–40 years old) presenting with complaints of ED. It is
medicine providers should be familiar with when diagnosing, important to identify the precise etiology of the ED before
counseling, and treating young men with erectile dysfunction. proceeding with further evaluation and treatment because the
work-up can be invasive and costly.
This article is part of the Topical Collection on Men’s Health

* Seth D. Cohen Definition

sethdcohenmd@gmail.com
Erectile dysfunction refers to the inability to achieve and
1
Department of Urology, NYU Langone Medical Center, maintain an erection adequate for intercourse. [1] Patients pre-
150 East 32nd Street, New York, NY 10016, USA senting with ED should be questioned carefully to rule out
84 Page 2 of 9 Curr Urol Rep (2015) 16: 84

other male sexual disorders including loss of libido, absence comers is typically of organic etiology, yet, in young men
of emission, absence of orgasm, and, most commonly, prema- presenting with ED, a psychogenic influence must be ruled
ture ejaculation because many times these disorders can pres- out. The main setback for most healthcare providers is to
ent concomitantly with ED. differentiate organic pathologies from psychological ones in
younger patients with ED, as this can be a difficult discussion
and a timely work-up.
Epidemiology All initial work-ups for ED should entail a detailed history,
which can be attained with the help of validated question-
ED is estimated to affect 20 % of men above 40 years of age, naires like the International Index of Erectile Function/
with the incidence increasing with increasing age. [2] Erectile Sexual Health Inventory for Men (IIEF/SHIM) scores. [9,
dysfunction has traditionally been seen as an age-dependent 10] All men should undergo a complete bio-psycho-social
problem. However, approximately 2 % of men are affected at evaluation. Younger patients with ED may wish to undergo
40 years of age but this may be a gross underestimation sec- psychological evaluation with an American Association of
ondary to reporting bias. [3] Another important reason for the Sexuality Educators, Counselors and Therapists (AASECT)-
rise in ED is the rapidly growing prevalence of diabetes certified sex therapist, as this disorder can be a lifelong con-
mellitus (DM) which is a major known risk factor for ED. dition. For young men with a diagnosis of psychogenic ED,
[4] An estimated 20–30 million American men are affected psychologic evaluation addresses the psychogenic contribu-
with ED of varying degrees of severity. [5] The Massachusetts tions to the clinical presentation. [11] It is well documented
Male Aging Study published in 1994 reviewed 1211 men in population studies that ED is associated with anxiety, de-
between the ages of 40 and 70; 52 % reported ED with pression, low degrees of self-esteem, negative outlook on life,
9.6 % having mild, 22.2 % moderate, and 17.2 % complete and self-reported emotional stress. [11] Even though the psy-
or severe ED. [5] ED, however, is not an inevitable result of chogenic ED patient likely benefits the most from this type of
aging; rather, as a man matures, it is likely that he will expe- evaluation and treatment, men with lifelong organic ED can
rience a neurovascular insult, trauma, and/or scarring resulting also see benefits from this type of therapy.
in ED. Erectile dysfunction may signal serious underlying and po-
tential life-threatening diseases, such as diabetes, hypertension,
cardiovascular disease, peripheral vascular disease, and other
Mechanism of Erection neurologic and endocrine disorders. In addition to a detailed
history and physical examination, a complete hormone evalua-
Penile erection occurs through a nitric oxide (NO)-mediated tion is performed to exclude testosterone deficiency, thyroid
mechanism. Penile cavernosal tissue contains non-adrenergic disease, hyperestrogenemia or hypoestrogenemia, or the pres-
non-cholinergic nerve terminals located within endothelial ence of a prolactinoma. A physical examination is performed,
cells that release NO, the main neurotransmitter involved in checking for the presence of anatomical defects like Peyronie’s
erections. [6] NO causes relaxation of the cavernosal smooth plaques/calcifications. Additional testing like quantitative and
muscle through a cyclic GMP-mediated (cGMP) reduction of qualitative testing measuring sensory/vibration, and hot and
intracellular calcium, after which cGMP gets degraded by cold perception to assess the integrity of the dorsal nerve
phosphodiesterase type 5 (PDE5). [6] Erections are main- branches of the pudendal nerve can be performed if warranted.
tained when cavernosal lacunar spaces become engorged with [12•] Once this is accomplished, the next step in the assessment
blood, compressing the subtunical venules against the tunica algorithm is to decide whether the ED is primarily organic or
vaginalis. To detumesce, adrenergic receptors are activated psychogenic in nature which may dictate the need for additional
leading to contraction of the cavernosal smooth muscle, which diagnostic testing (organic) or to go directly to psychogenic
reduces the diameter of the cavernosal artery thus reducing treatments.
blood flow, which then opens up the subtunical venules [7].

Categories of Erectile Dysfunction

Evaluation
Psychogenic Erectile Dysfunction
As suggested by Melman et al., an “erection is truly at least a
sensory-motor-neuro-hormonal-vascular-psycho-social-cul- The first diagnosis that practitioners jump to when they see a
tural-interpersonal event.” [8] When a young man comes into young man in the office with ED is psychogenic ED. Among
the office with ED, we classify him into two main groups: the major problems with this distinction are that it is based on
organic or psychogenic ED according to the underlying pa- an obsolete view that his ED is “all in his head.” [13] Psycho-
thology. Current dogma dictates that up to 80 % of ED in all genic ED is not necessarily a diagnosis of exclusion since
Curr Urol Rep (2015) 16: 84 Page 3 of 9 84

psychological pathology can be a result of or incorporated discern how severe the ED is to help determine the ap-
within an organic cause of ED. Traditional teaching states that propriate treatment regimen for that patient. Lastly,
a careful history can help to differentiate psychogenic from Peyronie’s disease and a history of pelvic/perineal trauma
organic erectile dysfunction. [13] may require further specific diagnostic testing then de-
In psychogenic ED, symptoms can develop quickly after an scribed below.
inciting event like job loss, marital/relationship stress, or more Intracavernosal injection (ICI) of vasoactive agents
commonly with younger men, a traumatic sexual event. A trau- combined with duplex ultrasound (US) provides reliable
matic sexual event can often lead to performance anxiety, which and detailed information on penile hemodynamics and
creates a heightened period of anxiety and stress during future vascular anatomy and is recommended as a first-line test
intimate moments. There is extensive literature demonstrating to evaluate penile arterial and veno-occlusive function.
how depression, stress, and anxiety are among the psycholog- [18, 19••] To measure the velocity of blood flow,
ical conditions that have clearly demonstrated major neuro- intracavernous injection is performed with or without
chemical and neuroendocrine changes in the brain. [14, 15] visual sexual stimulation. Medications used are prosta-
Changes in neurobiology would be expected then to contribute glandin E1, bimix (papaverine and prostaglandin), and
to impaired erectile function in these young men. trimix (papaverine, prostaglandin, phentolamine) to
Stress and anxiety lead to an increased cortisol and adren- achieve an erection similar to or better than can be
aline state similar to a “fight or flight” scenario. A heightened achieved at home.
sympathetic response leads to cavernosal smooth muscle con- Once an erection is achieved, penile Doppler ultraso-
traction and subsequently decreases erectile potential. This is nography (PDU) can measure the arterial diameter and
in contrast to a more organic cause of ED where symptoms are measure intracavernosal arteriole velocities. Criteria for
more insidious and can often be linked to comorbid conditions defining a normal erection response (based on PDU) ac-
like diabetes and high blood pressure or traumatic injury. [16] cording to Lue et al. included either cavernosal artery
Additional questioning in the history may reveal men with peak systolic velocity (PSV) [greater than or equal to]
psychogenic ED who report difficulty performing sexually 25 cm/s or an end-diastolic velocity (EDV) of <5 cm.
with one partner but not with another. It is important to deter- [20] A PSV<25 cm/s would be considered arterial inflow
mine whether these men can achieve a hard, rigid erection insufficiency, and an EDV>5 cm/s would be considered
during manual masturbation compared with during inter- as venous insufficiency. [20] For the neurological work-
course with their partner. up for organic ED, reflex conduction testing of the
Questioning about nocturnal and morning erections can be bulbocavernous reflex and dorsal nerve can help rule
quite inconstant in both the psychogenic and organic population. out neuro-scensory defects.
Thus, these questions can be asked in the complete history; how- (b) Penile tumescence and rigidity monitoring/Rigiscan:
ever, the validity of such information is variable. Nocturnal penile tumescence (NPT) monitoring,
Lastly, it is accepted that ED many times cannot be fully which describes the study of erections that occur with
dichotomized into psychogenic and organic categories. The nighttime sleep, was classically seen as a technique to
interview should assess whether ED is the primary source of assess physiologic erectile ability. [21] Traditionally,
the presenting complaint or secondary to some other aspects sleep laboratory nocturnal penile tumescence and ri-
of the sexual response cycle (e.g., desire, ejaculation, orgasm) gidity (NPTR) testing utilizes nocturnal monitoring
that may also relate to the clinical presentation. [17] The as- devices that measure the number of episodes, tumes-
sociation of decreased arousal, if present, may be explored as cent circumference change, maximal penile rigidity,
well and evaluated as to whether it preceded the development and duration of nocturnal erections. [22] In addition
of ED. to electromyography (EMG) monitoring, rapid eye
movement (REM) sleep and the presence or absence
Organic Erectile Dysfunction of hypoxia (sleep apnea) are documented. Important-
ly, documentation of REM sleep is done because of
To make the diagnosis of organic erectile dysfunction, there the observation that true erectile phenomena occurring
must be an anatomical/physiological defect that creates an during sleep are associated with the REM sleep
arterial inflow deficiency, venous incompetence, or a combi- phase. [22] Upon awakening, axial rigidity is mea-
nation of the two. sured along with photography of the erect penis at
maximal tumescence.
(a) Initial evaluation and work-up: While some have asserted that NPTR is the best
When working up a young man with ED after a psy- non-invasive method to differentiate organic from
chogenic cause has been ruled out, it is imperative to first psychogenic impotence, others have argued that com-
attain the etiology of the organic ED and second to plete dependence on NPTR values can be misleading.
84 Page 4 of 9 Curr Urol Rep (2015) 16: 84

[23–25] Nocturnal penile tumescence recording also selections of PDE5-I, based on patient’s needs and
has some limitations in anxiety and sleep disorders. preferences.
[26, 27] Moreover, the results from NPTR cannot The side effect profile of these three drugs is important to
assist in differentiating between arteriogenic and recognize and may affect patient safety and compliance. Since
venogenic erectile dysfunction. [24, 28] PDE5-I have an additive effects on the nitric oxide (NO) path-
(c) Dynamic infusion cavernosometry/cavernosography way, their use is contraindicated in patients taking any form of
(DICC) nitrates as they may produce life-threatening hypotension.
Cavernosometry has been used in the diagnostic eval- This is not as important in the young ED patient; however,
uation of selected patients who are suspected to have a the American Heart Association/American College of Cardi-
site-specific vasculogenic leak resulting from perineal or ology consensus panel recommended that nitrates not be ad-
pelvic trauma or who have had lifelong ED (primary ministered within 24 h after sildenafil dosing. [38] In addition,
ED). When used, it generally precedes consideration PDE5-I can cross-react with multiple different PDE receptors
for corrective penile vascular surgery. [29, 30] A pres- causing variable effects on olfaction (PDE1), insulin action
sure gradient more than 30 mmHg between the (PDE3), platelet aggregation, and vascular tone (PDE3,
cavernosal and brachial artery systolic occlusion pres- PDE5). [39] Because of the cross-reactivity of sildenafil and
sures is considered abnormal. The existence of veno- vardenafil with PDE6 receptors, patients should be counseled
occlusive dysfunction is indicated by: 1) the failure to about color changes in vision (chromatopsia) and more infre-
increase intracavernous pressure to the mean systolic quently, increased sensitivity to light and blurred vision. These
blood pressure with saline infusion or 2) the demonstra- visual effects are not seen with tadalafil and avanafil.
tion of a rapid drop of intracavernous pressure after ces- According to standard dosing recommendations for silden-
sation of saline infusion. Even if cavernosometry is a afil and vardenafil, patients are instructed to take the medica-
reliable test in the evaluation of patients with vascular tions on demand approximately 1 h before intended sexual
erectile dysfunction, it should not be used alone to decide activity. Tadalafil 20 mg can have effects lasting up to 36 h.
treatment. [31, 32] However, a daily dosing regimen has been approved for
tadalafil for men with concomitant ED and benign prostatic
hypertrophy (BPH) based on its extended half-life. This regi-
men provides patients with the ability to have sexual inter-
course on demand with greater spontaneity. [38, 40]
Treatment The abundance of choices poses the question, “which PDE5
inhibitor?” relevant for clinicians, patients, and their partners. A
Oral Therapy significant percentage of men initiating treatment will ultimate-
ly switch between inhibitors or discontinue therapy (poor com-
Among the many stated treatments on the market today, phos- pliance). Proper counseling of patients and their partners as to
phodiesterase type 5 inhibitors (PDE5-I), remain the most the appropriate treatment choice is paramount to optimizing
widely used oral agents and have great success rates, mainly compliance. It is widely accepted that there are no significant
due to their ease of administration and proven efficacy. PDE5- differences in the safety and efficacy of the four PDE5-I, al-
I, including sildenafil, tadalafil, vardenafil, and avanafil have though avanafil has shown great promise in reducing the typical
become first-line drug therapies for the treatment of ED [33]. side effects in younger men. [35••] This has led to the initiation
In men with psychogenic ED as well as with mild arterial of studies aimed at evaluating patient preferences.
insufficiency or mild venous leak, oral PDE5-I can be used to Strodeburg et al. (2006) showed high success rates when
overcome these deficiencies. Despite their similar modes of giving patients the freedom to try all available PDE5-I. [41]
action, PDE5-I differ in their biochemical properties, pharma- Similarly, Lunjunggren et al. (2007) evaluated 127 men at a
cokinetic profiles, and clinical performance. Most distinctive mean age of 60 years (range 36–79 years) who were given the
is their half-life, with sildenafil, vardenafil, and avanafil hav- option of taking any of three PDE5-I. [42] Seventy-five per-
ing half-lives of approximately 4–5 h, compared with cent of the men used only one drug; the others alternated
tadalafil, with a half-life of 17.5 h. [34•] The median time to between a short- and long-acting drug, depending on their
maximum concentration (t max) is 1 h for sildenafil and situation and preference. Of the 127 men, 109 (86 %) were
vardenafil, and 2 h for tadalafil. Median (t max) values as still using PDE5 inhibitors at the end of the 2-year period. The
low as 30 min have been reported with avanafil at the 50, most common reason for discontinuation of therapy was a
100 and 200 mg doses. [35••, 36] High-fat meal intake influ- return of satisfactory spontaneous erections. The authors con-
ences the absorption profiles of both sildenafil and vardenafil cluded that allowing patients to choose any of the three med-
but not with tadalafil or avanafil. [35••, 36, 37] The differences ications resulted in a high compliance rate over an extended
in their pharmacokinetic properties offer a basis for clinical period of time. [42]
Curr Urol Rep (2015) 16: 84 Page 5 of 9 84

Lastly, these medications may be only partially effective in with pure arterial inflow insufficiency. The procedure is de-
certain patients, and they have a considerable financial cost. signed to bypass the penile arterial blockage using a donor
[43•] In addition, they provide only symptomatic relief of ED artery (the inferior epigastric artery) and anastomosing it to
and do not offer a cure for the disease. Therefore, there is a the recipient artery (the dorsal penile artery). [54–58] In-
growing interest in developing therapies that offer a cure for creased perfusion pressure is theoretically communicated to
erectile dysfunction in younger patients. the cavernosal artery via perforating branches from the dorsal
artery. As it is the case in many aspects of surgery, patient
Intracavernosal Injection Therapy selection is the key to optimizing clinical outcomes. The best
candidates for surgery are younger patients with a history of
Alprostadil, the only FDA-approved injectable medication for blunt trauma to the pelvis, perineum, or penis who on evalu-
ED, is a synthetic form of a naturally occurring fatty acid, pros- ation have intact psychologic, neurologic, and hormonal
taglandin E1. Alprostadil binds to specific receptors on smooth work-up. [54–58]
muscle cells and activates intracellular adenylate cyclase to pro- Aside from preoperative Doppler ultrasonography of the
duce cAMP, which in turn induces tissue relaxation causing tu- carvernosal artery, additional information is needed such as
mescence of the penis. [44] After intracavernous injection, the presence of communicating branches from the dorsal to the
medication is locally metabolized by 96 % within 60 min and cavernosal artery, direction of flow through septal communi-
does not appreciably enter the peripheral circulation. [45] cators, dorsal artery diameters, and peak systolic velocities
Although intracavernosal injection (ICI) utilizes a small, which are critical in the selection of the best recipient dorsal
typically 31-gage needle, patients’ fear of injection often can artery. [54] Vascular assessment by dynamic infusion
produce a heightened sympathetic response, which dulls the cavernosometry/cavernosography (DICC) is required to dem-
response of the cavernous smooth muscle to intracavernous onstrate arterial pressure gradients between the brachial artery
agents. This can produce a false-negative result. [46] and the cavernosal arteries. [54] A pressure gradient more than
Alprostadil alone or in combination with papaverine and 30 mmHg between the cavernosal and brachial artery systolic
phentolamine are the three main combinations used for ICI. occlusion pressures is considered abnormal. The purpose of
When mono-therapy with alprostadil fails, combination therapy these tests is to rule out corporal-venous occlusive dysfunc-
offers a synergistic mechanism of the vasoactive agents to elicit tion. Following the DICC test, if the patient has pure arterial
maximal erectile responses. [47–49] In addition, combination insufficiency a selective internal pudendal arteriogram is per-
therapy has been used to circumvent side effects of utilizing formed to confirm the location of the obstructive lesion, which
mono-therapy with a certain agent (e.g., penile pain associated is typically within one or both of the cavernosal artery(ies).
with alprostadil and scar formation with papaverine). [58, 59]
Patients are prescribed a small dose of medication to inject, Some complications of this procedure are as follows: trau-
especially in patients with non-vasculogenic forms of ED. At matic disruption of the anastomosis is possible within the first
dosages of 10 to 20 mcg, alprostadil induces full erections in few weeks following surgery usually from blunt pelvic trau-
up to 80 % of patients with ED. [50] In-office self-injection ma. No effort is made to discourage normal nocturnal erec-
training and education is strongly encouraged before home tions. Other possible complications include decreased penile
injection, because the dropout rate for ICI is high. This oppor- sensation and pain secondary to injury to the dorsal nerves.
tunity may also be used to titrate medication toward a dosage [54] The risks of these complications have been diminished as
that safely yields an erection of sufficient rigidity for sexual techniques of carefully dissecting out the dorsal artery from
intercourse yet lasts no more than an hour. [51, 52] the dorsal penile neurovascular bundle have improved. Glans
Side effects of treatment are most commonly pain at the hyperemia is a rare complication.
injection site (in 11 % of patients), hematoma/ecchymosis A lack of standardized research on penile revascularization
(1.5 %), prolonged erection/priapism (1 to 5 %), and penile makes precise comparison of the published statistics difficult.
fibrotic lesions (2 %). [53] Perceived advantages of alprostadil There is also still no clear definition of a successful outcome
for intracavernous pharmacotherapy relative to other agents after revascularization surgery. A clear distinction must be
are lower incidences of prolonged erection, systemic side ef- made between cure rate (defined as complete success), im-
fects, and penile fibrosis. Some disadvantages with all three provement of erection (partial success), and complete failure.
formulations include lack of spontaneity with the partner and a
shortened medication half-life if not refrigerated. Inflatable Penile Implant

Penile Revascularization Penile implants traditionally have been seen as a “last resort”
treatment for men whom failed other treatment modalities.
Microvascular arterial bypass penile revascularization is a sur- However, there is a small population of men (i.e., post-pria-
gical procedure typically offered to men in there 20s and 40s pism, fractured penis, or pelvic floor trauma) that present the
84 Page 6 of 9 Curr Urol Rep (2015) 16: 84

dilemma of also having failed less invasive treatments. For lipoprotein (HDL) can also result from testosterone therapy.
these young men who deserve the right to be sexually active, Lastly, there may be cardiovascular risks associated with tes-
there is a roll for penile prosthetic devices. tosterone supplementation. [63, 64]
The ideal prosthesis would provide its recipient with a pe-
nis that resembles as closely as possible both normal penile
flaccidity and tumescence. Only a three-piece inflatable de- Stem Cell Therapy for ED
vice can approach this ideal. Three-piece prostheses have
paired corporeal cylinders, a scrotal pump, and an abdominal Once a young man with ED has failed oral and injection ther-
fluid reservoir. All three-piece devices provide penile girth apy, treatment options become bleak. Aside from penile re-
expansion and rigidity similar to that of a normal erection. vascularization or penile implantation, options are limited.
Ideally, discussions regarding the treatment of ED should Thus, there is a growing interest in additional therapies that
include the partner; however, this is not always possible espe- might offer a cure for the disease, one of which is stem cell
cially in the young man who may not have a life partner at the (SC) therapy. [65, 66••]
time of presentation. The patient should understand that a SCs have the potential to divide indefinitely having the abil-
penile prosthesis produces an erection-like state; however, ity to either stay a SC or differentiate into a specialized cell type,
the glans is not included in the erection. In addition, for some such as brain cell, red blood cell, or muscle cell. [67, 68] The
men the erection may be shorter than their normal erection, ability to regrow or regenerate damaged tissues depends on the
especially after a prior implant was removed for infection. In- various surrounding stimuli and factors. [67, 68] SCs are clas-
office stretched penile length measurements can help both the sified into (totipotent, pluripotent, multipotent, or unipotent)
physician and the patient to have an appropriate expectation of depending on their differentiation potential. [67, 68] Totipotent
their prosthetic erectile length. SCs have the greatest differentiation potential followed by plu-
ripotent SCs and multipotent SCs. Unipotent SCs are precursor
Hormone Supplementation Therapy cells within the developed tissue, and they can give rise to only
one cell type, such as epithelial cells. [67, 68]
Testosterone supplementation is indicated in young men who Embryonic SCs are pluripotent cells that have been studied
have signs and symptoms of hypogonadism accompanied by in erectile dysfunction research. Bochinski et al. had the first
subnormal serum testosterone levels. This should only be pre- study investigating the use of SCs in ED, and they investigat-
scribed after a thorough discussion of the risks of testosterone ed the effect of embryonic SCs on neurogenic ED induced by
supplementation in a young fertile male. cavernosal nerve injury in a rat model. The authors demon-
Testosterone supplementation seems to have its major ef- strated improved erectile function when embryonic SCs were
fect on libido rather than erectile function. [60–62] There are injected into the rat corpora cavernosa. [69] Given the ethical
three FDA-approved preparations of testosterone: transder- concerns with the use of embryonic SCs, no further studies
mal, intramuscular (IM) depot injection, and injectable pellets had been done using such cells.
placed into the adipose tissue of the upper buttocks. Testoster- Bahk et al. investigated the effect of intracavernosal injec-
one IM injection is the least expensive form of androgen sup- tion of umbilical cord SCs in seven human patients with dia-
plementation on the market today. However, this does not betes mellitus. [70] This demonstrated improved erectile func-
replicate the normal circadian rhythm of testosterone in young tion and was initially promising. Clinical trials on a larger
men. In fact, after initial injection, supra-physiologic levels of scale are needed including histological analysis where appli-
testosterone are noted for 72 h, then, a steady exponential cable in order to validate these results and clarify their exact
decline to sub-physiologic levels occurs by 10–12 days. These effects in humans. [70]
fluctuations in testosterone levels can be bothersome to pa- SC therapy represents a very promising treatment option
tients. Testosterone pellet therapy most predictably mimics the for ED patients whom are poor responders to the current FDA-
natural circadian rhythm of endogenous testosterone produc- approved treatments. Intracavernosal injection of SCs is the
tion and also has the highest compliance rates of all testoster- most commonly used method for delivery, in both preclinical
one supplementation modalities. and clinical trials. The issue of allogeneic vs. autologous
The most common side effect from transdermals and IM source needs to be further clarified. Among the different SCs
injections is local skin irritation. Other side effects can be used, adipose-derived stem cells (ADSC) represents the most
elevated estrogen levels leading to emotional lability and widely used and easiest SC to work with. [71] However,
breast tenderness. Infertility results from suppression of whether adipose-derived vs. embryonic vs. placental-derived
follicle-stimulating hormone (FSH) and LH resulting in stasis SCs is a better choice needs to be answered through additional
of spermatogenesis and endogenous testosterone production. comparative studies. Lastly, the timing and interval of SC
Polycythemia, increased platelet aggregation, increased low- injection represents another issue that will need to be further
density lipoprotein (LDL), and decreased high-density investigated. [71]
Curr Urol Rep (2015) 16: 84 Page 7 of 9 84

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